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PLX-4032, Vemurafenib, Zelboraf, Crizotinib, PF-2341066 and to help them make more significant discoveries. ">GISTs are tumors of connective tissue that arise primarily due to mutations in c-kit. The c-kit protein is a tyrosine kinase receptor for stem cell growth factor (scf), but mutations make it constitutively active turning on downstream signals that stimulate cell proliferation and, possibly, genomic instability. Approximately 85% of GISTs are due to c-kit mutations, but the remaining cases have mutations in platelet derived growth factor receptor a (PDGFRa). PDGFR is also a tyrosine kinase receptor and mutations make it constitutively active resulting in unrestrained cell proliferation and differentiation. For many years, the standard of care for treatment of GISTs was surgical resection because the tumors were highly resistant to any known chemotherapeutic agents. However, in recent years the development of tyrosine kinase inhibitors have allowed for chemotherapeutic treatment with a 40-70% response rate in metastatic or inoperable cases. Imatinib was the first tyrosine kinase inhibitor that was approved to treat GISTs. Imatinib was initially identified as a specific inhibitor of bcr-abl and approved to treat chronic myelogenous leukemia (see previous post). Later, it was discovered that imatinib is also a c-kit inhibitor and is extremely successful in treating most GISTs. However, as in chronic myelogenous leukemia, GISTs can become resistant to imatinib and progress. Sunitinib was developed as a second generation tyrosine kinase inhibitor to treat GISTs that had become resistant to imatinib. Sunitinib is a multi tyrosine kinase inhibitor with action against not only c-kit but also PDGFR. The drug can halt or even reverse disease progression in imatinib-resistant GISTs and was approved by the FDA in 2006 for that indication after compelling Phase III clinical trial results. GISTs were only treatable by surgical resection prior to the early 2000s. Imatinib was the first drug to be used to successfully treat GISTs due to its inhibitory action on c-kit. Unfortunately, many patients became resistant to treatment with imatinib within two years. Sunitinib is a second generation treatment for GISTs, which inhibits both c-kit and PDGFR. These two tyrosine kinase inhibitors have become favored, successful, front-line treatments for this rare but challenging disease. REFERENCES Nilsson B, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer. 2005;103(4):821-829. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-710. Williams LT (March 1989). “Signal transduction by the platelet-derived growth factor receptor”. Science 243 (4898): 1564–70. Nguyen SQ, Divino CM, Wang JL, Dikman SH (May 2006). “Laparoscopic management of gastrointestinal stromal tumors”. Surg Endosc 20 (5): 713–6. Demetri GD et al. (2006). “Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial”. Lancet 368 (9544): 1329–1338. RELATED POSTS Imatinib – the “magic bullet” for treatment of chronic myelogenous leukemia Second generation bcr-abl kinase inhibitors treat CML in the face of imatinib resistance Related to Tyrosine kinase inhibitors are the first effective treatments for gastrointestinal stromal tumors Imatinib – the “magic bullet” for treatment of chronic myelogenous leukemia INTRODUCTION Chronic myelogenous leukemia (CML) is a hematologic myeloproliferative cancer characterized by unregulated proliferation of white blood cells in the bone marrow and accumulation in ... Second generation bcr-abl kinase inhibitors treat CML in the face of imatinib resistance INTRODUCTION Shortly after imatanib was cleared by the FDA and entered clinical use as a successful treatment for chronic myelogous leukemia (CML), reports of drug-resistant ... Fostamatinib, a Syk inhibitor, shows promise in treating both B-cell neoplasms and autoimmune disorders INTRODUCTION Rheumatoid arthritis (RA) is a disabling and painful condition that affects approximately 1% of the world’s population. Onset usually occurs between the ages of ... To meet customers's needs and satisfaction, our purpose is to provide scientists world-wide an easy access to the most innovative life science reagents like PLX-4032, Vemurafenib, Zelboraf, Crizotinib, PF-2341066 and to help them make more significant discoveries.
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